Cholestyramine resin powder, which is the chloride salt of a basic anion exchange resin, is a cholesterol lowering agent intended for oral administration. Although cholestyramine is quite hydrophilic, it is insoluble in water and is not absorbed from the digestive tract. Cholestyramine is marketed by the Bristol-Myers Company as a powder under the tradename QUESTRAN. The powder is not taken in its dry form, but is always mixed with water or other fluids before ingesting. The recommended adult dose is four grams of cholestyramine resin from one to six times daily. QUESTRAN is available as a powder in packets of nine grams, four of which are relatively anhydrous cholestyramine resin. The remaining five grams comprise other additives such as sucrose, flavoring and other ingredients to make the powder more palatable.
Obviously, it would be greatly desirable if cholestyramine resin could be put into tablet form, thereby eliminating the need for both mixing the powder in water before ingesting, and adding additional materials to render the product palatable. It would be even more desirable if the cholestyramine resin could be rendered directly compressible into a tablet, since direct compression is by far the desired tableting method, when compared to either wet or dry granulation methods. However, only a very limited number of pharmaceutical substances possess enough cohesive strength and flowability to allow direct compression without previous granulation. In fact, it is estimated that only about 20 percent of all materials used for tableting in the pharmaceutical field may be directly compressed. In order to use this method to a greater extent, many more materials are modified either by treating the material in some special way during early stages of preparation, or by adding a direct compression vehicle that mixes with the active ingredient and forms a flowable and easily compressible mixture. It is, of course, desirable to be able to directly compress a composition without addition of direct compression vehicles. Thus, it would be desirable to be able to directly compress cholestyramine resin into a tablet, preferably without the aid of direct compression vehicles.
Even if one were to successfully directly compress cholestyramine into a tablet, there is an additional problem that must still be overcome. Cholestyramine is extremely hygroscopic, which makes cholestyramine tablets very difficult to swallow. A cholestyramine tablet placed in the mouth swells rapidly by readily taking up the available moisture. A very dry mouth results and the tablet adheres to the tongue, and thus cannot be comfortably swallowed. Accordingly, it would be desirable to coat the tablet so as to render it easy to swallow.
Attempts to coat cholestyramine tablets, however, encounter difficulties because coatings normally comprise either water or an organic solvent. It is impossible to coat cholestyramine tablets with a water-based coating because the hygroscopic tablets would swell during the coating process. Although it is not difficult to coat cholestyramine with a solvent-based coating, cholestyramine has an affinity for the solvent which is retained even after the drying processes. That is, the cholestyramine resin retains the solvent in the tablet matrix itself at levels generally considered unacceptable. Such solvents often include an alcohol (e.g., ethanol) and methylene chloride. While retained alcohol might be acceptable, retained methylene chloride is not. Thus, there is a need for a coating which is neither water nor solvent based, and which imparts swallowability to cholestyramine or other pharmaceutical tablets.
U.S. Pat. No. 3,383,237 to Tuerck teaches a solvent-free coating applied in a molten state at temperatures of 60.degree. C. to 130.degree. C. Tuerck teaches a coating composition comprising 60-90 percent by weight of polyethylene glycol (PEG) with an average molecular weight of 1000-9000, and 10-40 percent by weight of one or more synthetic or natural resins and gums which are miscible in a solution of PEG at temperatures of 45.degree. C.-200.degree. C. The application method described comprises tumbling tablets in a rotating coating pan, preheating and maintaining the tablets at a temperature of 30.degree. C. to 40.degree. C., continuously applying the molten composition at temperatures of 60.degree. C. to 130.degree. C. onto the tablets until the desired coat thickness is obtained, and then tumbling/cooling the tablets to congeal the coating.
A second publication, Tuerck et al, Formula Modifications in a Solvent-Free Tablet Film Coat, J. Pharm. Sci., Vol. 62, 1534-37 (1973), describes the results of a screening study of 17 materials, including stearic acid, used to modify a basic hot-melt composition containing either 10 percent shellac and 90 percent PEG or 20 percent shellac and 80 percent PEG. The materials were added individually to the two basic hot-melt compositions at a level of 10 percent of the total composition. No other levels were evaluated. The modified compositions were then applied to tablets using the equipment and process described in the Tuerck patent. Of the additives evaluated, Tuerck et al found that only castor oil, cocoa butter and isopropyl myristate improved the basic formulations.
Polyethylene glycol has a somewhat unpleasant burning taste. It has also been found, that a high content of polyethylene glycol in tablet coatings result in tablets that are rough looking or bumpy textured. Moreover, increasing the polyethylene glycol content past certain percentages appears to decrease the durability of the coating as evidenced by cracking during handling. In general, PEG is not used in tablet coating at high concentrations because of objectionable taste and odor. Thus, it would be desirable to formulate a solvent-free coating that eliminated the disadvantages resulting from high levels of polyethylene glycol.
Accordingly, it is an object of this invention to provide a process for producing directly compressible cholestyramine tablets.
Another object of this invention is to provide agglomerated cholestyramine particles that can be directly compressed into a tablet having essentially no excipients or additives.
Yet another object of this invention is to provide a smooth, solvent-free coating that contains low amounts of polyethylene glycol and can be used to coat tablets such as cholestyramine.